The main objective of our study was to investigate
the role of increased inflammation and oxidative
stress over endothelial functions with transthoracic
echocardiographic evaluation of the CFR and HPDFR
in patients with FM. The primary endpoint of the study
was to evaluate endothelial dysfunction which should
be determined by CFR and HPDFR measurements
to prove FM as a cardiovascular risk factor. The
CFR is a combined measurement of the vasodilator
capacity of coronary microcirculation, which is an
independent predictor of long-term prognosis
of atherosclerosis.[
15] We evaluated endothelial
dysfunction which was revealed by decreased levels
of CFR and HPDFR in patients with FM. Our study
results showed that HPDFR and CFR values were
significantly reduced in FM patients. In addition,
conventional CRP values were also higher in these
patients. Similarly, Bote et al.[
16] confirmed that FM
patients had an inflammatory state accompanied by
an altered stress response. This is mainly manifested
by high circulating levels of interleukin (IL)-8 and
CRP (in 100% of the FM group). There is also
an increased release of inflammatory cytokines
(IL-1b, tumor necrosis factor-alpha, IL-6, IL-10,
IL-18 and monocyte chemoattractant protein-1) by
monocytes, and enhanced activation of the functional
capacity of neutrophils (chemotactic, phagocytic and
fungicidal activities).[
16] The etiopathogenesis of FM is
multifactorial. Apart from neurohormonal and genetic
factors, increased inflammatory activity and oxidative
stress are known to play a role in the development of
FM.[
16,
17] Thus, data on CRP are also controversial.
A large-scale study showed a positive association
between CRP and FM.[18] However, this association
was attenuated after adding body mass index and comorbidities in the model. The fact that these
conditions, which are included in the pathophysiology
of endothelial dysfunction and atherosclerosis,
suggests that the endothelial functions of patients
with FM may also be impaired and, thus, FM and
endothelial dysfunction may accompany. Endothelial
cells and endothelium-derived cytokines are other
modulators of inflammation. A study by Mertoglu et
al.[
5] revealed that the level of endocan, a proteoglycan
produced by endothelial cells, was significantly higher
in patients with FM, compared to healthy controls.
Increased levels of cytokines induced by inflammatory
reaction and catecholamine-induced endothelial
damage including microvascular spasm may be related
with the pathophysiological mechanisms of decreased
CFR in FM patients.[
8] Vascular endothelial cells
modulate the vascular tone either by secreting relaxing
or constructing mediators. The ET1 is one of the
potent vasoconstrictor peptides which is oversecreted
by the endothelium and the vascular smooth cells
as a result of inflammatory conditions. These levels
increase in patients with FM.[
8]
Coronary microvascular spasm plays a major
role in affecting myocardial ischemia in patients
without obstructive coronary artery disease and
also associated with female predominance.[19]
Similarly, Suwaidi et al.[20] reported that coronary
endothelial dysfunction without obstructive coronary
lesions was significantly associated with advanced
cardiovascular disease. Likewise, endothelial and
microvascular dysfunction, abnormal neurohormonal
activity, and small vessel disorders may lead to
coronary slow flow which ranges from 1 to 6%
among patients with suspected coronary artery
disease.[21] The coronary circulation may be sensitized
to the circulating vasoconstrictor catecholamines
by microvascular endothelial dysfunction in terms
of inflammatory processes. Nevertheless, chronic
pain may impair coronary circulation as a result of
immoderate triggering of sympathetic nervous system
(SNS) in FM patients.[22] Increased sympathetic
activity can change cardiovascular responses and
cause endothelial dysfunction. Nitric oxide, which
is produced by catalyzing L-arginine, has a critical
function in vasodilatation. Activated SNS decreases
endothelial-derived vasodilatation caused by a loss
of NO bioavailability in the vessel wall, although
this process limits the relaxation ability of the
artery and impairs the smooth cell functions.[23] The
link between the immune and nervous systems is implicated in the pathophysiology of FM-related
vascular disorders.
Flow-mediated vasodilation (FMD) test is the
most accepted non-invasive test which reflects
arterial endothelial-mediated vasomotor function.[24]
Due to possible side effects of the administered
drugs or invasive patterns of procedures to evaluate
the endothelial functions, endothelial function
measurement through FMD shows high accuracy.[25]
Cardiovascular diseases are considered major
causes of morbidity and mortality.[26] Patients with
FM can be also evaluated regarding the cardiovascular
risk factors. Reducing the pain and diminishing
the severity of disease can be crucial to prevent
cardiovascular risk factors in patients with FM. Our
findings suggest that CFR is a possible predictor of
long-term prognosis of atherosclerosis in FM patients
which would call attention to the long-term impacts
of living with FM. Further studies are, therefore,
required to confirm FM as a cardiovascular risk
factor.
The fact that the entire population in the patient
group was female is the main limitation to this
study. During the study period, no male patients
were admitted to either Physical Medicine and
Rehabilitation or Rheumatology outpatient clinics of
our center with the diagnosis of FM. Additionally, the
menstrual cycle of the patients were not considered
and different hormonal phases may have affected
cardiovascular variables. Finally, the findings of
our study are only preliminary data and further
large-scale, prospective studies are needed for future
considerations about coronary flow dynamics in FM
patients.
In conclusion, chronic stress and pain augment
the sympathetic activity, resulting in endothelial
dysfunction and increasing the cardiovascular risk.
Endothelial dysfunction should be evaluated by
measuring coronary flow reserve in FM patients.
Ethics Committee Approval: This was a prospective
and single-center study which was approved by the Medicana
International Istanbul Hospital Ethics Committee (date:
03.11.2021, no: 022) and was conducted by the principles
of the Helsinki Declaration. Ethical consent had also been
obtained for intravenous drug administration during the CFR
measurements.
Patient Consent for Publication: A written informed
consent was obtained from each patient.
Data Sharing Statement: The data that support the
findings of this study are available from the corresponding
author upon reasonable request.
Author Contributions: Idea/concept, data collection
and/or processing, design: G.G.; Design, analysis and/or
interpretation: E.B.K.; Literature review, writing the article,
critical review: B.Ş.
Conflict of Interest: The authors declared no conflicts
of interest with respect to the authorship and/or publication
of this article.
Funding: The authors received no financial support for
the research and/or authorship of this article.
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